Effects of 8-monochloro-3-beta-diethylaminoethyl-4-methyl-7-ethoxycarbonylmethoxy coumarin (AD6) on the coronary circulation in the dog

Aporti, F.; Finesso, M.; Granata, L

doi:10.1016/s0031-6989(78)80037-x

Cited by 32 publications

(10 citation statements)

References 6 publications

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“…Cloricromene, originally called AD6, is a coumarine derivative, which produces coronary dilation (Aporti et al, 1978), stimulates prostacyclin production from human cultured endothelial cells (Dejana et al, 1982) and lowers thromboxane B2 synthesis from platelet (Galli et al, 1980). Furthermore cloricromene improves survival rate, decreases plasma myocardial depressant factor accumulation and reduces macrophage TxB2 synthesis in splanchnic artery occlusion shock (Squadrito et al, 1988;Sturniolo et al, 1989;1991).…”

Section: Introductionmentioning

confidence: 99%

RETRACTED: Cloricromene, a coumarine derivative, protects against collagen‐induced arthritis in Lewis rats

Cuzzocrea

Mazzon

Bevilaqua

et al. 2000

British J Pharmacology

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1 The aim of the present study was to investigate the e ects of cloricromene, a coumarine derivative, in rats subjected to collagen-induced arthritis. 2 Collagen-induced arthritis (CIA) was induced in Lewis rats by an intradermal injection of 100 ml of the emulsion (containing 100 mg of bovine type II collagen) (CII) and complete Freund's adjuvant (CFA) at the base of the tail. On day 21, a second injection of CII in CFA was administered. 3 Lewis rats developed an erosive hind paw arthritis when immunized with CII in CFA. Macroscopic clinical evidence of CIA ®rst appeared as peri-articular erythema and oedema in the hind paws. The incidence of CIA was 100% by day 27 in the CII challenged rats and the severity of CIA progressed over a 35-day period with radiographic evaluation revealing focal resorption of bone together with osteophyte formation in the tibiotarsal joint and soft tissue swelling. 4 The histopathology of CIA included erosion of the cartilage at the joint margins. Treatment of rats with cloricromene (10 mg kg 71 i.p. daily) starting at the onset of arthritis (day 23), delayed the development of the clinical signs at days 24 ± 35 and improved histological status in the knee and paw. 5 Immunohistochemical analysis for iNOS, COX-2, nitrotyrosine and for poly (ADP-ribose) synthetase (PARS) revealed a positive staining in in¯amed joints from collagen-treated rats. The degree of staining for iNOS, COX-2, nitrotyrosine and PARS were markedly reduced in tissue sections obtained from collagen-treated rats, which had received cloricromene. 6 Radiographic signs of protection against bone resorption and osteophyte formation were present in the joints of cloricromene-treated rat. 7 This study provides the ®rst evidence that cloricromene, a coumarine derivative, attenuates the degree of chronic in¯ammation and tissue damage associated with collagen-induced arthritis in the rat.

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Section: Introductionmentioning

confidence: 99%

RETRACTED: Cloricromene, a coumarine derivative, protects against collagen‐induced arthritis in Lewis rats

Cuzzocrea

Mazzon

Bevilaqua

et al. 2000

British J Pharmacology

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“…AD 6 (8-monochloro-3-beta-diethylaminoethyl-4-methyl-7-etoxy-carbonylmethoxy coumarin) is an experimental drug which is known to have a vasodilatory effect on dog coronary arteries [1]. Further studies have described other properties of AD 6 including its capability to inhibit platelet aggregations and release due to various agents [2 4].…”

Section: Introductionmentioning

confidence: 99%

The coumarin derivative AD6 inhibits the release of arachidonic acid by interfering with phospholipase A2 activity in human platelets stimulated with thrombin

et al. 1990

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AD6 is a coumarin derivative which is able to inhibit platelet aggregation and release due to various agonists as adrenaline, PAF, Ca++ ionophore and others. It has been demonstrated that this compound reduces the production of free arachidonate and diglyceride from human platelets pulse-labeled with radioactive arachidonic acid thus suggesting a possible interference with the activity of phospholipase A2 and/or phospholipase C. The present report indicates that the drug has no effect on the increase of the labeling of phosphatidic acid which takes place when platelets pulse-labeled with arachidonic acid are stimulated with thrombin. Furthermore, AD6 is not able to cause changes on the metabolism of phosphoinositides monitored using platelets pre-labeled with [3H] inositol. These observations exclude the possibility that AD6 interferes with phospholipase C activity. Experiments with platelets pulse-labeled with arachidonate suggest that AD6 inhibits phospholipase(s) A2 activity or modulate negatively one or more processes involved in its activation.

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“…Thus, the reduction in myocardial damage observed with the low dose of cloricromene may be related to a modification of processes that occurred during reperfusion alone. Furthermore, a contribution of coronary vasodilatation (Aporti et al, 1978) to the anti-ischaemic effects of cloricromene cannot be excluded. With respect to anti-aggregatory activity, while cloricromene demonstrated cardioprotection at both 30 and 300 tLg kg-1 min ', only the high dose of cloricromene caused an inhibition of ADP or collagen-induced platelet aggregation.…”

Section: Discussionmentioning

confidence: 99%

“…Cloricromene weakly stimulates prostacyclin production in human cultured endothelial cells and rat thoracic aortic rings (Dejana et al, 1982), reduces thromboxane B2 release from platelets and inhibits platelet aggregation induced by various agents (Galli et al, 1980;Prosdocimi et al, 1985;. In addition, cloricromene inhibits both polymorphonuclear adhesion to endothelial cells and superoxide generation (Bertocchi et al, 1989), and causes coronary dilatation in the dog (Aporti et al, 1978).…”

Section: Introductionmentioning

confidence: 99%

Dissociation of the anti‐ischaemic effects of cloricromene from its anti‐platelet activity

Lidbury

Cirillo

Vane

1993

British J Pharmacology

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1 Cloricromene is a non-anticoagulant coumarin derivative with anti-platelet and anti-leukocyte properties, which has beneficial effects in various models of ischaemia and shock. 2 We have assessed the effects of cloricromene on (a) ex vivo platelet aggregation, and (b) infarct size using a model of myocardial ischaemia in the anaesthetized rabbit.3 Cloricromene (1-1000 tgkg' min'I for 15min) induced a dose-dependent inhibition of ex vivo platelet aggregation, causing only a minimal increase in heart rate and no change in mean arterial blood pressure. The inhibitory activity was considerably stronger when platelet aggregation was induced by collagen than by ADP. 4 Cloricromene inhibited ex vivo platelet aggregation in rabbits pretreated with indomethacin (5 mg kg-') and this inhibition persisted for 30-60 min.5 The model of myocardial ischaemia involved 1 h occlusion of the first antero-lateral branch of the left coronary artery followed by 2 h of reperfusion. Infusion of cloricromene (30 or 300 gg kg-' min-'), ibuprofen (80 iLg kg-' min') or vehicle began 15 min prior to occlusion, and continued throughout the experiment.6 While area at risk was similar for all groups studied, cloricromene (30 or 300 ftg kg' min-') or ibuprofen caused a reduction in infarct size, and decreased myeloperoxidase activity in the tissue of the infarcted myocardium.7 Cloricromene at 300 pg kg-' min-' also reduced the occlusion-induced elevation of the ST-segment of the rabbit electrocardiogram, and inhibited platelet aggregation ex vivo. Ibuprofen or cloricromene at 30 fg kg-' min'-had no effect on either the ST-elevation or platelet reactivity.8 Thus, cloricromene exhibits a cardioprotective activity via an inhibition of leukocyte infiltration, in the presence (300 tLg kg-l min-') or absence (30 ltg kg'-min-') of inhibition of platelet activity ex vivo.The anti-aggregatory activity of cloricromene acts via a mechanism that is either different from, or in addition to, inhibition of cyclo-oxygenase, and is of long duration.

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Effects of 8-monochloro-3-beta-diethylaminoethyl-4-methyl-7-ethoxycarbonylmethoxy coumarin (AD6) on the coronary circulation in the dog

Cited by 32 publications

References 6 publications

RETRACTED: Cloricromene, a coumarine derivative, protects against collagen‐induced arthritis in Lewis rats

RETRACTED: Cloricromene, a coumarine derivative, protects against collagen‐induced arthritis in Lewis rats

The coumarin derivative AD6 inhibits the release of arachidonic acid by interfering with phospholipase A2 activity in human platelets stimulated with thrombin

Dissociation of the anti‐ischaemic effects of cloricromene from its anti‐platelet activity

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